Cardiovascular illness is a major health care problem in modern society. Coronary artery disease often leads to myocardial infarction and heart failure. In the USA, chronic heart failure is the most frequent reason for hospitalisation in people over the age of 65.
Chronic heart insufficiency (CHI) is a complex syndrome and influences many systems of the body. The most common reason for CHI in elderly is the coronary heart disease [Ho K K L, Anderson K M, Kannel W B, et al. Survival after the onset of congestive heart failure in Framingham heart study subjects. Circulation 1993; 88: 107-115]. In case of CHI, a series of pathophysiological modifications of haemodynamic, metabolic or functional type occur [Anker S D, Coats A J S. Metabolic, functional and haemodynamic staging for CHF. Lancet 1996; 348: 1530-1531].
The prevalence of CHI in the population reaches approximately 0.3-2% in total [Cowie M R, Mosterd A, Wood D A, Deckers J W, Poole-Wilson P A, Sutton G C, et al. The epidemiology of heart failure. Eur Heart J 1997; 18:208-225]. Worldwide, the number is therefore estimated to be 15 million patients. The prevalence of CHI increases with age and reaches more than 10% in persons being older than 80 years [Kannel W B, Belanger A J. Epidemiology of chronic heart failure. Am Heart J 1991; 121: 951-957]. Predisposing factors of CHI are hypertonus, diabetes mellitus, smoking, adipositas and hyperlipidemia.
Megestrol acetate (MA, Megace®) is a synthetically produced derivative of the naturally occurring steroid hormone progesterone. Megace® is a white, crystalline substance having the chemical name 17-α-acetoxy-6-methylpregna-4,6-diene-3,20-dione (C24H32O4) and a molecular weight of 384.5. Megestrol acetate has the following formula:

Megace® is an orally active solution and is primarily excreted via the kidneys. The bio-availability is not completely elucidated. Megestrol acetate is an appetite stimulant that acts by a still unknown mechanism. Initially, Megace® was used for the inhibition of malignant post-menopausal hormone dependent tumours of the breast [Gregory E J, Cohen S C. Megestrol acetate therapy for advanced breast cancer. J Clin Oncol 1985; 3:155-160. Benghiat A, Cassidy S A. Megestrol acetate in the treatment of advanced post-menopausal breast cancer. Eur J Surg Oncol 1986 12: 43-45, Goss P E. Pre-clinical and clinical review of vorozole, a new third generation aromatoase inhibitor. Report. Breast Cancer Res Tr 1998; 49: S59-S65] and the prostate [Keller J, White J M. A phase III randomised comparative trial of megestrol acetate v. diethylstilbestrol in stage D2 prostatic cancer. Preliminary results. Proc Am Soc Clin Oncol 1986, 5:421. Bonomi P, Pessis D, Bunting N, et al. Megestrol acetate used as primary hormonal therapy in stage D prostatic cancer. Semin Oncol 1985; 12 (Suppl 1): 36-39]. While using it, an increase of weight and an appetite stimulation was discovered as side effects. Initially, a dose of 30 mg/d [Stoll B A. Progestin therapy of breast cancer: comparison of agents. Br Med J 1967; 3: 338-341] was used. In 10% of the patients an increase of weight of at least 5% was observed after six weeks in case of a dose of 60-180 mg/d [Alexieva-Figusch J, Van Glise H A. Progestin therapy in advanced breast cancer: Megestrol acetate—An evaluation of 160 treated cases. Cancer 1980; 46: 2369-2372]. Further studies confirmed the appetite stimulating effect [Tchekmedyian N S, Tait N, Moody M, Aisner J. High dose megestrol acetate: a possible treatment for cachexia. JAMA 1987; 257: 1195-1198]. In case of a later standard dose of 160 mg Megace®/d in nearly one third of the patients an increase of the weight was found [Keller J, White J M. A phase III randomised comparative trial of megestrol acetate v. diethylstilbestrol in stage D2 prostatic cancer. Preliminary results. Proc Am Soc Clin Oncol 1986, 5:421. Bonomi P, Pessis D, Bunting N, et al. Megestrol acetate used as primary hormonal therapy in stage D prostatic cancer. Semin Oncol 1985; 12 (Suppl 1): 36-39, Tchekmedyian N S, Tait N, Moody M, et al. Appetite Stimulation with megestrol acetate in cachectic cancer patients. Sem Oncol 1986; (Suppl 4): 37-43]. In higher dose of 1600 mg Megace®/d, in 81% of all patients (>2 kg, median 5.5 kg) and in more than 90% of the patients with mama carcinoma, an increase of weight was reached. Thus, a dosage and time dependent effect of Megace® exists, wherein the dosage dependent effect is not yet statistically proven. For further information regarding Megace® and dosage options, see, for example, http://www.medsafe.govt.nz/profs/Datasheet/m/Megacetab.htm
Megace® has been used for several years successfully in cachexia of patients having mamma carcinoma or other malignant tumours. In Germany, the medicament is only registered for the therapy in progressed mamma carcinoma. For a specific therapy in patients with mama carcinoma in phase IV for improving the quality of life the dosages 160 mg/d, 800 mg/d and 1600 mg/d were compared in the CALGB-study and 160 mg/d was found as the optimal dosage [Komblinth A B, Hollis D R, Zuckerman E, et al. Effect of megestrol acetate on quality of life in a dose-response trial in woman with advanced breast cancer. J Clin Oncol 1993; 11: 2081-2089].
In studies with patients having AIDS-cachexia, von Roenn et al. [Von Roenn J H, Armstrong D, Kotler D P, et al. Megestrol Acetate in patients with AIDS-related cachexia. Ann Inter Med 1994; 121: 393-399] studied 232 patients with MA in different dosages: 100 mg/d, 400 mg/d, and 800 mg/d. In this study, 800 mg/d was found as optimal dosage. For a human, a dosage of 13.3 mg/kg/d is recommended. It could be shown that the most reasonable dosage for the therapy of cachexia (best weight increase in relation to side effects) in the human is 800 mg/d (corresponds to approximately 13 mg/kg/d at 60 kg body weight) as overall dosage in one or two applications [Oster M H, Enders S R, Samuels S J, et al. Megestrol acetate in patients with AIDS and Cachexia. Ann Intern Med 1994; 121: 400-408, Von Roenn J H, Armstrong D, Kotler D P, et al. Megestrol Acetate in patients with AIDS-related cachexia. Ann Inter Med 1994; 121: 393-399].
Recently, a novel substance herein below designated as “novel Megace®” has been introduced that is also designated as “Megace® ES”. Novel Megace® essentially is the same medication as the commonly used megestrol acetate, but having a micro-crystalline structure which significantly improves resorption. Both oral suspensions contain the same active agent, however, Megace® ES has a different formulation why resorption is significantly improved. Par Pharmaceutical Companies, Inc. manufactures this advanced formulation, as disclosed in the PCT application WO 03/086354 A1. The improvement is caused by a nanoparticulate composition comprising megestrol acetate and preferably at least one surface stabilizer associated with the surface of the drug. These nanoparticulate megestrol particles have an effective average particle size of less than about 2000 nm. This advanced formulation, in a preferred embodiment thereof, utilises NanoCrystal™ Dispersion technology to improve the bioavailablity of the drug, compared to currently available formulations of the product, as disclosed in WO 04/050059 as a low viscosity liquid dosage form comprising particles of an active agent, a surface stabilizer, and a pharmaceutically acceptable excipient, carrier, or a combination thereof, wherein the active agent particles have an effective average particle size of less than about 2 microns and the dosage form has a viscosity of less than about 2000 mPa·s at a shear rate of 0.1 (1/s). NanoCrystal® Dispersion is a trademark of Elan Corporation, plc, Dublin, Ireland. Megace® is a registered trademark of Bristol-Myers Squibb Company licensed to Par Pharmaceutical, Inc. The U.S. Food and Drug Administration (FDA) has approved Megace® ES for the treatment of anorexia, cachexia, or an unexplained, significant weight loss in patients with a diagnosis of acquired immunodeficiency syndrome (AIDS). Recent data have shown that the bioavailability of the original formulation is reduced substantially when taken on an empty stomach. With Megace® ES, this reduction in bioavailability is minimized in the fasted state, resulting in improved bioavailability in patients who have not eaten. Megace® ES 625 mg/5 ml and megestrol acetate oral suspension 800 mg/20 ml are bioequivalent in a fed state. The effect of novel Megace® appears to be faster than compared to the initial Megestrol acetate (herein designated as “old” (common) Megace®).
For Megace®, anti-androgene, anti-estrogene and small glucocorticoid-similar effects are assumed [Alexieva-Figusch J, Van Glise H A. Progestin therapy in advanced breast cancer: Megestrol acetate—An evaluation of 160 treated cases. Cancer 1980; 46: 2369-2372].
The standard therapy with medicaments in CHI consists in general in particular in the application of diuretics, ACE-blockers, optionally angiotensin, Il-receptor-antagonists, beta-blockers, and/or aldosteron-antagonists as well as medicaments for the prophylaxis and therapy of arrhythmias and angina pectoris. In addition, increasingly pace markers and implantable defibrillators are used. In patients with most severe CHI, surgical therapies with assist devices and heart transplantations are taken into account. A main aim of the therapy is, to improve life expectancy and life quality of the patients.
In cases of severe CHI the one year mortality in earlier studies despite therapy with vasodilators and digitalis reached 52%, in cases of additional application of an ACE-blocker still 36% per year [The CONSENSUS Trial Study group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429-1435]. Despite further improved therapies including ACE-blockers and Beta-blockers, CHI of intermediate severity (New York Heart Association Class II-III) is today still related to a one year mortality of approximately 15-30% [Braunwald E (ed), et al. Heart Disease. A textbook of cardiovascular medicine. 6th edition. WB Saunders Company 2001; chapter 17: 546-547, Johnson D, Jin Y, Quan H, et al. Beta-Blockers and angiotensin-converting enzyme inhibitors/receptor blockers prescriptions after hospital discharge for heart failure are associated with decreased mortality in Alberta, Canada. J Am Coll Cardiol 2003; 42: 1438-1445].
Improved treatments of heart failure (acute or chronic) and of myocardial infraction are sought for. It is therefore an object of the present invention to provide an improved treatment of myocardial infarction and of heart failure in order to reduce severity and mortality of the diseases. It is furthermore an object of the present invention to provide for an improved therapy of heart insufficiency.
The object of the present invention is, in one particular aspect thereof, solved by the use of Megace® or a pharmaceutically acceptable salt thereof, optionally with appropriate adjuvants and additives for the therapy of improvement of heart function after myocardial infarction and in heart failure. Furthermore, the object of the present invention is solved by the use of Megace® or a pharmaceutically acceptable salt thereof, optionally with appropriate adjuvants and additives for the production of a medicament for the therapy of cardial cachexia and/or heart insufficiency, in particular following myocardial infarction.
In the literature there is no claim or evidence that Megace® is useful in the treatment of myocardial infarction or heart failure.
Based on an animal model, the influence of the appetite stimulant Megace® in heart failure after a myocardial infarction was therefore analysed. For this, the following factors were particularly taken into account:
1. Mortality
2. Infarction size and cardial function
3. Organ weight in comparison
Surprisingly, it could be found during these experiments, that Megace® did not have an effect on cardiac cachexia per se (it did not increase body weight), but it improved cardiac function as reflected in improved heart weights and LVEF values as well as survival. This effect was particularly (and thus preferably) present when the microcrystalline novel form of Megace®, i.e. the advanced formulation of megestrol acetate oral suspension (Megace® ES) was used. In order to obtain valid weight measurements, a diuretic was furthermore administered to all animals of the Megace®-study. The use of diuretics is a routine measure in patients with heart insufficiency.
Megace® useable according to the present invention can be provided in any number of forms suitable for administration. Suitable pharmaceutically acceptable forms comprise salts or pre or pro-forms of Megace®.
Examples of pharmaceutically acceptable salts comprise without limitation non toxic inorganic or organic salts such as acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enantate derived from heptanoic acid, formiate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, chloride derived from hydrochloric acid, bromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methanesulfonic acid, naphtaline-2-sulfonate derived from naphtaline-2-sulfonic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, phthalate derived from phthalic acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, sulphate derived from sulphuric acid, tartrate derived from tartaric acid, toluene-p-sulfate derived from p-toluene-sulfonic acid and others. Such salts can be produced by methods known to someone of skill in the art and described in the prior art.
Other salts like oxalate derived from oxalic acid, which is not considered as pharmaceutically acceptable can be appropriate as intermediates for the production of Megace® or a pharmaceutically acceptable salt thereof.
Megace® or a pharmaceutically acceptable salt thereof can be bound to microcarriers or nanoparticles in parenterals like, for example, to finely dispersed particles based on poly(meth)acrylates, polylactates, polyglycolates, polyamino acids or polyether urethanes. Parenteral formulations can also be modified as depot preparations, e.g. based on the “multiple unit principle”, if Megace® or a pharmaceutically acceptable salt thereof is introduced in finely dispersed, dispersed and suspended form, respectively, or as a suspension of crystals in the medicament or based on the “single unit principle” if Megace® or a pharmaceutically acceptable salt thereof is enclosed in a formulation, e.g. in a tablet or a rod which is subsequently implanted. These implants or depot medicaments in single unit and multiple unit formulations often consist out of so called biodegradable polymers like e.g. polyesters of lactic and glycolic acid, polyether urethanes, polyamino acids, poly(meth)acrylates or polysaccharides.
Adjuvants and carriers added during the production of the medicaments usable according to the present invention formulated as parenterals are preferably aqua sterilisata (sterilised water), pH value influencing substances like, e.g. organic or inorganic acids or bases as well as salts thereof, buffering substances for adjusting pH values, substances for isotonisation like e.g. sodium chloride, sodium hydrogen carbonate, glucose and fructose, tensides and surfactants, respectively, and emulsifiers like, e.g. partial esters of fatty acids of polyoxyethylene sorbitans (for example, Tween®) or, e.g. fatty acid esters of polyoxyethylenes (for example, Cremophor®), fatty oils like, e.g. peanut oil, soybean oil or castor oil, synthetic esters of fatty acids like, e.g. ethyl oleate, isopropyl myristate and neutral oil (for example, Miglyol®) as well as polymeric adjuvants like, e.g. gelatine, dextran, polyvinylpyrrolidone, additives which increase the solubility of organic solvents like, e.g. propylene glycol, ethanol, N,N-dimethylacetamide, propylene glycol or complex forming substances like, e.g. citrate and urea, preservatives like, e.g. benzoic acid hydroxypropyl ester and methyl ester, benzyl alcohol, antioxidants like e.g. sodium sulfite and stabilisers like e.g. EDTA.
When formulating the medicaments usable according to the present invention as suspensions in a preferred embodiment thickening agents to prevent the setting of Megace® or a pharmaceutically acceptable salt thereof, tensides and polyelectrolytes to assure the resuspendability of sediments and/or complex forming agents like, for example, EDTA are added. It is also possible to achieve complexes of the active ingredient with various polymers. Examples of such polymers are polyethylene glycol, polystyrol, carboxymethyl cellulose, Pluronics® or polyethylene glycol sorbit fatty acid ester. Megace® or a pharmaceutically acceptable salt thereof can also be incorporated in liquid formulations in the form of inclusion compounds e.g. with cyclodextrins. In particular embodiments dispersing agents can be added as further adjuvants. For the production of lyophilisates scaffolding agents like mannite, dextran, sucrose, human albumin, lactose, PVP or varieties of gelatine can be used.
In as far as Megace® is not included in a liquid drug formulation in its basic form it can be employed within the parenterals in the form of its acid addition salt solvates.
A further important systemic application formulation is peroral administration in the form of tablets, hard or soft gelatine capsules, coated tablets, powders, pellets, microcapsules, compressed oblongs, granulates, cachets, lozenges, chewing gum or sachets. These solid perorally administered formulations can also be formulated as retard and depot systems, respectively. Comprised therein are medicaments with a content of one or more micronised active agents, diffusion and erosion forms based on matrix, e.g. by using fats, waxy or polymeric substances or so called reservoir systems. If the medicament is formulated to release Megace® over a prolonged period of time retarding agents and agents for the controlled release, respectively, can be added like film or matrix forming substances, for example, ethylcellulose, hydroxypropyl methyl cellulose, poly(meth)acrylate derivatives, (e.g. Eurdragit®), hydroxypropyl-methylcellulose phthalate both in organic solutions and in the form of aqueous dispersions. In this context bioadhesive preparations should also be mentioned wherein an extended dwelling time in the body is caused by the intimate contact with the mucous membranes of the body. An example of a bioadhesive polymer is, e.g. the group of Carbomere®.
For the purpose of a controlled release of Megace® or a pharmaceutically acceptable salt thereof within the different segments of the gastro-intestinal tract it is possible to employ a mixture of pellets which release at different locations. The medicament formulation can be coated, for example, with mixtures of films, substances, compounds or compositions soluble in gastric juice and resistant to gastric juice, respectively. The same purpose of affecting the release in different sections of the gastro-intestinal tract can also be reached with appropriately produced coated tablets with a core, wherein the coating releases the active ingredient in gastric juice rapidly and the core releases the active ingredient in the environment of the small intestine. The aim of a controlled release in different sections of the gastro-intestinal tract can also be achieved by multiple coated tablets. Mixtures of pellets with differentially releasable active agent can be filled into, for example, hard gelatine capsules.
A further adjuvant employed in the production of compressed formulations like e.g. tablets, hard and soft gelatine capsules as well as coated tablets and granules are, for example, counter glue agents, lubricating agents and separating agents, dispersion agents like e.g. flame dispersion silicon dioxide, disintegrants like, e.g. various types of starch, PVP, cellulose, ester as granulating or retarding agent like, e.g. waxy and/or polymeric substances based on Eudragit®, cellulose or Cremophor®.
Furthermore medicaments formulated for peroral administration can comprise antioxidants, sweetening agents like, e.g. saccharose, xylite or mannite, taste correcting agents, flavorants, preservatives, colouring agents, buffering agents, direct compression excipients, microcrystalline cellulose, starch, hydrolysed starch (e.g. Celutab®), lactose, polyethylene glycol, polyvinylpyrrolidone, dicalcium phosphate, lubricants, fillers like, e.g. lactose or starch, binders in the form of lactose, types of starch like e.g. wheat or corn and rice starch, respectively, derivatives of cellulose like, e.g. methyl cellulose, hydroxypropyl cellulose or silica, talcum, stearate like, e.g. magnesium stearate, calcium stearate, talkum, siliconised talkum, stearic acid, cetyl alcohol or hydrogenated fats etc. A variety of substances are known to someone of skill in the art which can be added to medicaments for the formulation for peroral administration.
In a further embodiment Megace® or a therapeutically acceptable salt thereof can also be formulated as an oral therapeutic system, in particular based on osmotic principles like, e.g. GIT (gastro-intestinal therapeutic system) or OROS (oral osmotic system).
Effervescent tablets or tabs are also among compressed formulations, which can be perorally administered and which are both rapidly dissolvable or suspendable in water and are rapidly drinkable instant drug formulations.
Perorally administrated formulations also include solutions e.g. drops, juices and suspension which can be produced according to methods known in the art and which can comprise—beside the already mentioned adjuvants and additives for the increase of the stability—preservatives and if desired flavouring agents for easier ingestion and colouring agents for better distinction as well as antioxidants and/or vitamins and sweetening agents like sugars or artificial sweeteners. This also applies to dried juices which are prepared with water prior to use. In a preferred embodiment of a formulation of the medicaments of the present invention an ingestible liquid formulation can also comprise an ion exchange resin.
In a preferred embodiment of the present invention, the Megace® is selected from common Megace® and/or novel Megace®. As an example, Megace® is commercially produced by several companies as generic medicament. For the present study, two forms of Megace® were used that were obtained from the company PAR Pharmaceuticals (see above).
In yet another preferred embodiment of the present invention, the CHI is based on coronary heart disease.
Yet another preferred embodiment of the present invention is characterised in that the medicament is applied orally. Preferably, Megace® or a pharmaceutical acceptable salt thereof is applied in a dosage of between 30 mg/d and 2000 mg/d, preferably between 100 mg/d and 1600 mg/d, most preferred 300 to 800 mg/d. The active ingredient can be administered in one or several doses per day; alternatively the active ingredient can be administered in larger time intervals. Also preferably, Megace® or a pharmaceutical acceptable salt thereof is applied in a dosage of between 4 and 15 mg/kg/d. The active ingredient can be administered in one or several doses per day; alternatively the active ingredient can be administered in larger time intervals.
In another important embodiment of the present invention, Megace® or a pharmaceutical acceptable salt thereof is applied in combination with drugs typically used in CHI, such as suitable diuretics, vasodilators, digitalis, an ACE-inhibitor, an angiotensin-II receptor antagonist, a beta-blocker, an aldosterone antagonist, an endothelin receptor antagonist, a xanthin oxidase inhibitor, a statin (a HMG-CoA reductase inhibitor) and/or bile-acid resins (such as cholestyramine (Questran®) and colestipol (Colestid®)), cholesterol absorption inhibitors (such as Ezetimibe (Zetia®), nicotinic acid (niacin), and fibric acid derivatives (fibrates), such as fenofibrate (TriCor®) and gemfibrozil (Lopid®). Preferably, the diuretic is furosemide.
The invention also relates to a composition comprising Megace® or a pharmaceutical acceptably salt thereof in combination with a suitable diuretic, a vasodilator, digitalis, an ACE-blocker, and/or a beta-blocker. Preferably, the diuretic is furosemide.
The compositions according to the present invention comprising one or more suitable diuretic, a vasodilator, digitalis, an ACE-blocker, and/or a beta-blocker can be produced by someone of skill in the art in one of the formulations disclosed above for Megace® and can be mixed with respectively indicated adjuvants and additives. In a further aspect the invention also relates to the spatially and/or temporally separated administration of the respective active ingredients.
It was a main goal of the study underlying the present invention as well as other studies, to reach a reduced mortality in addition to an increase of weight and a better stability of the patient's weight. Since in most patients having chronic heart insufficiency oedema occur, nearly all human patients with heart insufficiency are undergoing a therapy with a diuretic [Cowie M R, Mosterd A, Wood D A, Deckers J W, Poole-Wilson P A, Sutton G C, et al. The epidemiology of heart failure. Eur Heart J 1997; 18:208-225]. Prior studies have shown that also in diseased rats, that are used as a model in present invention, oedema occur which would interfere with the measurements of weight and the comparisons. Thus, all infarct animals were given furosemide together with drinking water. It can therefore be expected that the changes in weight are with a high probability related to an increase or decrease of fat, muscle or bone mass and are not caused by oedema. In addition, the results as indicated in Example 2, below, show that furosemide has no effect on the echocardiographically determined heart function.
In an infarct model sub-acute infarctions having a chronic progress develop. The generation of a CHI in human in any cases is caused by a myocardial infarct. Thus, the infarct model allows for representative results for chronic heart insufficiency. In the present invention, the red infarct model for the production of a chronic heart insufficiency was therefore used.
In another aspect of the present invention, furosemide was used together with Megace® in order to provide for a further improved combination therapy.
Another aspect of the present invention is related to a method for improving cardic function and/or the treatment of chronic heart insufficiency in a mammal, comprising providing an effective amount of megestrol acetate or a pharmaceutically acceptable salt thereof to said mammal, optionally with suitable adjuvants and additives, as already explained above. Preferably, said mammal is a human. More preferably, said megestrol acetate is selected from common megestrol acetate oral suspension (Megace®) and/or Megace® ES.
According to said method according to the present invention, said chronic heart insufficiency can result from a cardiomyopathy, in particular chronic heart insufficiency resulting from a cardiomyopathy due to myocardial infarction.
Preferably, said effective amount of megestrol acetate or pharmaceutically acceptable salt thereof is applied orally. More preferably, said megestrol acetate or a pharmaceutical acceptable salt thereof is applied in a dosage of between 30 mg/d and 2000 mg/d, preferably between 100 mg/d and 1600 mg/d, most preferred 300 to 800 mg/d. More preferably, said megestrol acetate or a pharmaceutical acceptable salt thereof is applied in a dosage of between 4 and 15 mg/kg/d.
Another aspect of the present invention is related to a method according to the present invention, wherein said megestrol acetate or a pharmaceutical acceptable salt thereof is applied in combination with drugs typically used in CHI, like a suitable diuretic, a vasodilator, digitalis, an ACE-inhibitor, an angiotensin-II receptor antagonist, a beta-blocker, an aldosterone antagonist, endothelin receptor antagonist, a xanthin oxidase inhibitor, a statin (a HMG-CoA reductase inhibitor) and/or bile-acid resins, cholesterol absorption inhibitors, nicotinic acid, and fibric acid derivatives. Preferably said diuretic is furosemide.
The following conclusions can be drawn from the present experiments. The myocardial infarction induced in rats nearly always leads to a proven heart failure in these rats. Rats having an surgically induced myocardial infarction have a lower chance of survival compared to sham-surgery rats. Novel megestrol acetate significantly improved the heart function parameters LVEF and FS in infarction surgery rats in comparison to placebo. Novel megestrol acetate significantly improved the survival in infarction surgery rats in comparison to placebo.
The following examples and figures are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventors to function well in the practice of the invention, and thus can be considered preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed without departing from the spirit and scope of the invention as set out in the appended claims. For the purposes of the present invention, all references as cited are incorporated herein by reference in their entireties.